Manufacture of alpha-tocopherol

ABSTRACT

A process for the manufacture of (all-rac)-α-tocopherol by the acid-catalyzed reaction of trimethylhydroquinone with isophytol or phytol is characterized by carrying out the reaction in the presence of methane trisulphonate as the catalyst in an organic solvent. The product of the process is the most active and industrially most important member of the vitamin E group.

The present invention is concerned with a novel process for themanufacture of (all-rac)-α-tocopherol by the acid-catalyzed reaction oftrimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH) in asolvent. As is known, (all-rac)-α-tocopherol (or as it has mostly beendenoted in the prior art, “d,l-α-tocopherol”) is a diastereoisomericmixture of2,5,7,8-tetramethyl-2-(4′,8′,12′-trimethyl-tridecyl)-6-chromanol(α-tocopherol), which is the most active and industrially most importantmember of the vitamin E group.

Many processes for the manufacture of “d,l-α-tocopherol” (referred to assuch in the literature reviewed hereinafter) by the reaction of TMHQwith IP or PH in the presence of a catalyst or catalyst system and in asolvent or solvent system are described in the literature. Theseprocesses go back to the work of Karrer et al., Bergel et al. as well asSmith et al. [see Helv. Chim. Acta 21, 520 et seq. (1938), Nature 142,36 et seq. (1938) and, respectively, Science 88, 37 et seq. (1938) andJ. Am. Chem. Soc. 61, 2615 et seq. (1939)]. While Karrer et al. carriedout the synthesis of d,l-α-tocopherol from TMHQ and phytyl bromide inthe presence of anhydrous zinc chloride (ZnCl₂; a Lewis acid), not onlyBergel et al. but also Smith et al. used TMHQ and PH as startingmaterials. In the following years mainly modifications, e.g. alternativesolvents and Lewis acids, were developed. From the work of Karrer et al.there was developed in the year 1941 a technically interesting processfor the manufacture of d,l-α-tocopherol which was based on the reactionof TMHQ with IP in the presence of the catalyst systemZnCl₂/hydrochloric acid (HCl) (U.S. Pat. No. 2,411,969). Laterpublications, e.g. Japanese Patent Publications (Kokai) 1985/054380,1985/064977 and 1987/226979 [Chemical Abstracts (C.A.) 103, 123731s(1985), C.A. 103, 104799d (1985) and, respectively, C.A. 110, 39217r(1989)], describe this reaction in the presence of zinc and/or ZnCl₂ anda Brönsted (protonic) acid, such as a hydrohalic acid, e.g. HCl,trichloroacetic acid, acetic acid and the like, especially ZnCl₂/HCl, asthe catalyst system. Disadvantages of these and further publishedprocesses featuring ZnCl₂ in combination with a Brönsted acid are thecorrosive properties of the acids and the contamination of the wastewater with zinc ions as a result of the large amount of ZnCl₂ requiredfor the catalysis.

The manufacture of d,l-α-tocopherol by the reaction of TMHQ with phytylchloride, PH or IP in the presence of boron trifluoride (BF₃) or itsetherate (BF₃.Et₂O) is described in German Patents 960,720 and 1,015,446as well as in U.S. Pat. No. 3,444,213. However BF₃ too has corrosiveproperties.

Also, the reaction of TMHQ with IP or PH in the presence of a Lewisacid, e.g. ZnCl₂, BF₃ or aluminium trichloride (AlCl₃), a strong acid,e.g. HCl, and an amine salt as the catalyst system is described inEuropean Patent Publication (EP) 100,471. In an earlier patentpublication, DOS 2,606,830, the IP or PH is pretreated with ammonia oran amine before the reaction with TMHQ in the presence of ZnCl₂ and anacid is effected. In both cases corrosion problems occur.

A further interesting method for the manufacture of d,l-α-tocopherolfrom TMHQ and IP comprises using an isolated TMHQ-BF₃ or —AlCl₃ complexand a solvent mixture featuring a nitro compound (DOS 1,909,164). Thisprocess avoids to a large extent the formation of undesired by-productsbecause it involves mild reaction conditions. The yield ofd,l-α-tocopherol from a process using IP and the solvent mixturemethylene chloride/nitromethane is given as 77%. However, the use ofsuch a solvent mixture is disadvantageous.

The manufacture of d,l-α-tocopherol by the reaction of TMHQ with IPusing cation exchange resin complexes of metal ions (Zn²⁺, Sn²⁺ andSn⁴⁺) is disclosed in Bull. Chem. Soc. Japan 50, 2477-2478 (1977);amongst other disadvantages it gives the product in unsatisfactoryyields.

The use of macroreticular ion exchangers, e.g. Amberlyst® 15, as thecatalyst for the reaction of TMHQ with IP is described in U.S. Pat. No.3,459,773. However, the d,l-α-tocopherol could not be obtained in therequisite purity.

EP 603,695 describes the manufacture of d,l-α-tocopherol in liquid orsupercritical carbon dioxide by the reaction of TMHQ with IP or PH inthe presence of acidic catalysts, such as ZnCl₂/HCl and ion exchangers.The reported yields are unsatisfactory.

The reaction in the presence of a catalyst system which consists ofiron(II) chloride, metallic iron and HCl gas or aqueous solution isdescribed in DOS 2,160,103 and U.S. Pat. No. 3,789,086. The formation ofless by-products is advantageous compared with the aforementionedprocess using ZnCl₂/HCl. However, corrosion problems and chloridecontamination are equally disadvantageous.

An interesting alternative for the reaction of TMHQ with IP tod,l-α-tocopherol comprises using trifluoroacetic acid or its anhydrideas the catalyst (EP 12824). Although in this process the avoidance ofHCl is achieved, the catalyst is relatively expensive.

The use of the heteropoly acid 12-tungstophosphoric or 12-tungstosilicicacid as the catalyst for the reaction of TMHQ with IP was described forthe first time in React. Kinet. Catal. Lett. 47(1), 59-64 (1992).d,l-α-Tocopherol could be obtained, using various solvents, in about 90%yield.

A further process described in the literature [EP 658,552; Bull. Chem.Soc. Japan 68, 3569-3571 (1995)] for the synthesis of d,l-α-tocopherolis based on the use of a various lanthanide trifluoromethanesulphonates(triflates), e.g. scandium trifluoromethanesulphonate, as the catalystfor the reaction. With up to about 10% excess of IP this process givesyields up to 98%.

The use of ion-exchanged bentonite, montmorillonite or saponite throughtreatment with e.g. scandium chloride and other metal salts (yttrium,lanthanum, etc.) as the catalyst for the reaction of TMHQ with IP or PHhas as a disadvantage the need for a large amount of catalyst [EP677,520; Bull. Chem. Soc. Japan 69, 137-139 (1996)].

According to the Examples of EP 694,541 the reaction of TMHQ with IP toα-tocopherol can be achieved in high yields and with a high productpurity when such solvents as carbonate esters, fatty acid esters andcertain mixed solvent systems are employed, the exemplified catalysisbeing effected by ZnCl₂/HCl. Disadvantages in this process are, inaddition to the contamination of the waste water by zinc ions, the usuallarge “catalyst amount” of ZnCl₂ used.

According to WO 97/28151 the acid-catalyzed reaction of TMHQ with IP canbe performed in a cyclic carbonate or α-lactone as the solvent. Thepreferred catalyst is a mixture of orthoboric acid and oxalic, tartaricor citric acid, or boron trifluoride etherate.

WO 98/21197 describes the manufacture of d,l-α-tocopherol from TMHQ andIP using bis(trifluoromethylsulphonyl)imide or a metal salt thereofoptionally together with a strong Brönsted acid, as catalyst in suchtypes of aprotic solvents as aliphatic and cyclic ketones or esters, andaromatic hydrocarbons.

Using the same kind of bis(trifluoromethylsulphonyl)imide catalyst ithas been shown in EP 1,000,940 that the d,l-α-tocopherol manufacturingprocess can also be realized in supercritical carbon dioxide or nitrousoxide as the solvent.

From the foregoing review it is evident that most of the previouslyknown processes have considerable disadvantages. Thus, corrosionproblems occur in all processes in which such acid catalysts as borontrifluoride are used. Toxicity problems with the boron trifluorideadducts also occur, and when iron or zinc is used there is acontamination of the waste water with the metal ions which is today nolonger acceptable. In some processes the formation of undesiredby-products, e.g. phytyltoluenes, chlorophytols, and products of thedehydration of IP or PH, i.e. so-called phytadienes, is an especiallyserious problem: the selectively of the reaction is unsatisfactory. Inmost cases the yields are unsatisfactory.

The object of the present invention is to provide a process for themanufacture of (all-rac)-α-tocopherol by the reaction oftrimethylhydroquinone with isophytol or phytol in the presence of acatalyst and in a solvent which does not have the disadvantages ofpreviously known procedures. In this respect, it is necessary that thecatalyst used has no, or at least a much reduced, corrosive action, isnon-toxic, does not contaminate the environment, e.g. with chlorinatedby-products or heavy metal ions, and catalyzes the desired reaction asselectively as possible, with as little as possible co-production ofsuch by-products as phytadienes, and in high yields. Furthermore, thecatalyst should display its activity in small, really catalytic, amountsand should be readily separable and re-usable several times.

This object of the present invention is achieved by carrying out thereaction of trimethylhydroquinone with isophytol or phytol in thepresence of methane trisulphonate, of the formula CH(SO₃H)₃, as thecatalyst in an organic solvent.

Accordingly, the present invention is concerned with a process for themanufacture of (all-rac)-α-tocopherol by the acid-catalyzed reaction oftrimethylhydroquinone with isophytol or phytol, which process ischaracterized by carrying out the reaction in the presence of methanetrisulphonate as the catalyst in an organic solvent.

Methane trisulphonate, the compound used as the catalyst in the processof the present invention, is a known compound and can be prepared fromacetone or acetanilide in oleum, as described in e.g. J. Prakt. Chem.336, 373-374 (1994). The acidity of this and further alkanepolysulphonates is discussed in Z. Naturforsch. 51b, 1691-1700 (1996):see compound 24 in Table II therein.

In principle are all types of solvents useable for Friedel-Craftsreactions can be used as the solvents in the process of the presentinvention. In particular, however, polar aprotic organic solvents aresuitably used, such as dialkyl and alkylene carbonates, e.g. dimethyland diethyl carbonate, and ethylene, propylene and 1,2-butylenecarbonate, respectively; aliphatic esters, e.g. butyl acetate; aliphaticketones, e.g. diethyl ketone; and lactones, e.g. γ-butyrolactone; andmixtures of two or more of such solvents. Most preferred are biphasicsolvent systems comprising on the one hand a polar aprotic organicsolvent and on the other hand a non-polar aprotic organic solvent,examples of the latter being above all aliphatic hydrocarbons,particularly alkanes. Especially preferred such biphasic solvent systemsare those comprising ethylene carbonate or propylene carbonate or1,2-butylene carbonate, or a mixture of two or all three of these polaraprotic organic solvents, as the one (polar aprotic organic solvent)phase, and hexane, heptane or octane as the other (non-polar aproticorganic solvent) phase, especially ethylene carbonate and heptane,propylene carbonate and heptane, and a mixture of ethylene and propylenecarbonate and heptane.

The amount of the methane trisulphonate catalyst is conveniently about0.01 mole % to about 0.1 mole %, preferably about 0.0125 mole % to about0.08 mole %, of the amount of educt trimethylhydroquinone orisophytol/phytol, whichever is in the lesser molar amount, generally theisophytol or phytol.

The process is conveniently effected at temperatures from about 80° C.to about 160° C., preferably from about 90° C. to about 150° C.,especially from about 100° C. to about 142° C.

Furthermore, the molar ratio of trimethylhydroquinone to isophytol orphytol is conveniently about 1.25:1 to about 2.2:1, preferably about1.5:1 to about 2:1.

If the process is carried out in a biphasic solvent system, especiallyone consisting of a polar aprotic organic solvent, such as and aspreferred, a cyclic carbonate, e.g. ethylene carbonate, propylenecarbonate, 1,2-butylene carbonate or a mixture of two or all three ofthese cyclic carbonates, and a non-polar aprotic organic solvent such asan aliphatic hydrocarbon, e.g. hexane, heptane or octane, then thevolume ratio of the non-polar solvent to the polar solvent isconveniently in the range from about 1:10 to about 5:1, preferably 1:3to about 5:1, most preferably from about 1:1.25 to about 2:1. Moreover,when mixtures comprising ethylene carbonate and propylene carbonate areused for the one phase, the volume ratio of ethylene carbonate topropylene carbonate is suitably in the range of about 1:100 to about100:1. preferably about 1:10 to about 10:1, most preferably about 1:1.

Conveniently about 0.5-2 ml, preferably about 0.75-1.25 ml, mostpreferably about 0.9-1.1 ml, of a polar aprotic organic solvent are usedper mmol of trimethylhydroquinone.

The process is conveniently carried out under an inert gas atmosphere,preferably gaseous nitrogen or argon.

The actual reaction generally lasts for about 0.5 to about 2.5 hours,preferably about 0.75 to 1.5 hours.

The process in accordance with the invention can be carried outbatchwise or continuously, and in general operationally in a very simplemanner, for example by adding isophytol or phytol, as such or insolution, portionwise to a mixture of the catalyst, thetrimethylhydroquinone and the solvent, e.g. the biphasic solvent system.The catalyst can be added in solid form or, preferably, as an aqueoussolution. The rate at which the isophytol or phytol is added is notcritical. Conveniently, isophytol or phytol, preferably as such, isadded continuously over a period from about 5 minutes to about 1 hour,preferably from about 10 to 30 minutes. After completion of theisophytolphytol addition and an appropriate subsequent reaction periodthe working-up can be effected by procedures conventionally used inorganic chemistry.

If desired, the obtained (all-rac)-α-tocopherol can be converted intoits acetate, succinate, poly(oxyethylene)succinate, nicotinate andfurther known application forms by standard procedures [see, forexample, the 5^(th) Edition of Ullmann's Encyclopedia of IndustrialChemistry, Vol. A 27, pages 484-485 (VCH Verlagsgesellschaft mbH,D-69451 Weinheim, 1996)].

The process in accordance with the invention enables the catalyst usedto be separated readily and to be reused several times. Furtheradvantages in the use of the catalyst in the process are the high yieldsof the process product (all-rac)-α-tocopherol, the avoidance ofcorrosion, the avoidance of waste water contamination with heavy metalions, the high selectivity as well as the enabled ready isolation of theproduced (all-rac)-α-tocopherol from the mixture after reaction.

The process in accordance with the invention is illustrated by thefollowing Example:

EXAMPLE 1

7.55 g (50 mmol) of trimethylhydroquinone (purity 99.7%), 40 g ofethylene carbonate (or propylene carbonate) and 50 ml of heptane wereintroduced into a 200 ml four-necked flask equipped with a refluxcondenser, a water separator, a mechanical stirrer and an argongasification means and heated to reflux temperature (bath temperature140° C.) under an argon atmosphere. After the addition of methanetrisulphonate as an aqueous solution (for 0.05 mole % of CH(SO₃H)₃ basedon the molar amount of subsequently added isophytol 4.23 mg=391 μl ofcatalyst were used), 12.026 ml (33 mmol) of isophytol were added at arate of 0.6 ml/minute. Thus the volume ratio of trimethylhydroquinone toisophytol was about 1.5:1. Thereafter the heptane was distilled off andthe mixture was heated to 125-130° C. for 30 minutes, then cooled to 80°C. 50 ml of heptane were added to the ethylene carbonate phase. Thereaction mixture was stirred for a further 10 minutes at 50° C. Theheptane layer was then separated and evaporated under reduced pressureto give (all-rac)-α-tocopherol as a viscous oil in a yield shown in thefollowing Tables 1 and 2 in which EC signifies ethylene carbonate, PCsignifies propylene carbonate and IP signifies isophytol: TABLE 1 Amountof catalyst (mole % relative to IP) Solvent Yield (%) 0.16 EC + heptane98.2 0.056 EC + heptane 97.2 0.05 EC + heptane 95.3 0.05 PC + heptane91.2

TABLE 2 Duration of Ratio EC:heptane addition of IP in (g:ml) minutesYield (%) 10:80 20 99.2 10:80 60 97.7 20:70 20 96.1 10:50 20 92.4 20:5020 94.5 40:50 20 95.3

If desired, the crude product can be converted into its acetate bystandard procedures.

1. A process for the manufacture of (all-rac)-αtocopherol comprisingcarrying out an acid-catalyzed reaction of trimethylhydroquinone withisophytol or phytol in the presence of methane trisulphonate as thecatalyst in an organic solvent, the amount of the methane trisulphonatecatalyst being about 0.01 mole % to about 0.1 mole % of the amount ofeduct trimethylhydroquinone or isophytol/phytol, whichever is in thelesser molar amount.
 2. A process according to claim 1, wherein thesolvent is a polar aprotic organic solvent, or a mixture of two or moreof such solvents, or a two-phase solvent system comprising a polaraprotic organic solvent and a non-polar aprotic organic solvent.
 3. Aprocess according to claim 2, wherein the solvent is a biphasic solventsystem comprising ethylene carbonate, propylene carbonate or1,2-butylene carbonate, or a mixture of two or all three of these polaraprotic organic solvents, as the one solvent phase, and hexane, heptaneor octane as the other (non-polar aprotic organic solvent) solventphase.
 4. A process according to claim 2, wherein the solvent is abiphasic solvent system of which the volume ratio of the nonpolaraprotic organic solvent to the polar aprotic organic solvent is in therange from about 1:10 to about 5:1.
 5. A process according to claim 1,wherein the amount of the methane trisulphonate catalyst is about 0.0125mole % to about 0.08 mole % of the amount of educt trimethylhydroquinoneor isophytol/phytol, whichever is in the lesser molar amount.
 6. Aprocess according to claim 1, wherein the molar ratio oftrimethylhydroquinone to isophytol or phytol is about 1.25:1 to about2.2:1.
 7. A process according to claim 1, wherein the reaction iseffected at temperatures from about 80° C. to about 160° C.
 8. A processaccording to claim 1, wherein about 0.5-2 ml of a polar aprotic organicsolvent are used per mmol of trimethylhydroquinone.
 9. A processaccording to claim 1, wherein the process is carried out under an inertgas atmosphere.
 10. A process according to claim 1, wherein the processis carried out batchwise or continuously, and by adding isophytol orphytol, as such or in solution, portionwise to a mixture of thecatalyst, the trimethylhydroquinone and the solvent.
 11. A processaccording to claim 2, wherein the polar aprotic organic solvent isselected from the group consisting of a dialkyl or alkylene carbonate;an aliphatic ester; an aliphatic ketone; and a lactone; and thenon-polar aprotic organic solvent, if present, is an alkane.
 12. Aprocess according to claim 11, wherein the dialkyl or alkylene carbonateis selected from the group consisting of dimethyl carbonate, diethylcarbonate, ethylene carbonate, propylene carbonate and 1,2-butylenecarbonate; the aliphatic ester is butyl acetate; the aliphatic ketone isdiethyl ketone; the lactone is γ-butyrolactone; and the alkane, ifpresent, is selected from the group consisting of hexane, heptane, andoctane.
 13. A process according to claim 3, wherein the solvent is abiphasic solvent system of ethylene carbonate and heptane, of propylenecarbonate and heptane, or of a mixture of ethylene and propylenecarbonate and heptane.
 14. A process according to claim 4, wherein thevolume ratio of the non-polar aprotic organic solvent to the polaraprotic organic solvent is in the range from about 1:3 to about 5:1. 15.A process according to claim 14, wherein the volume ratio of thenon-polar aprotic organic solvent to the polar aprotic organic solventis in the range from about 1:1.25 to about 2:1.
 16. A process accordingto claim 6, wherein the molar ratio of trimethylhydroquinone toisophytol or phytol is about 1.5:1 to about 2:1.
 17. A process accordingto claim 7, wherein the reaction is effected at temperatures from about90° C. to about 150° C.
 18. A process according to claim 17, wherein thereaction is effected at temperatures from about 100° C. to about 142° C.19. A process according to claim 8, wherein about 0.75-1.25 ml of apolar aprotic organic solvent are used per mmol oftrimethylhydroquinone.
 20. A process according to claim 19, whereinabout 0.9-1.1 ml of a polar aprotic organic solvent are used per mmol oftrimethylhydroquinone.
 21. A process according to claim 9, wherein theinert gas atmosphere is nitrogen or argon.